Insulin exhibits short-term anti-inflammatory but long-term proinflammatory effects in vitro.
Although insulin is indispensable for maintaining glucose homeostasis, it is still controversial whether or not a high concentration of insulin is deleterious. We examined the effect of insulin on the transcriptional activity of NF-kappaB, which mediates the expression of a variety of inflammation/coagulation-related genes using hepatocyte cell lines in vitro. We found that insulin (1 nM) alone caused minimal increase in NF-kappaB-mediated transcription. On the other hand, when cells were simultaneously treated with proinflammatory cytokines such as TNFalpha, the following dual effect of insulin was observed: short-term (6h) suppressive, and long-term (36 h or later) stimulatory effects. The former effect was transient and appears to be mediated by the phosphatidylinositol 3 kinase (PI(3)K) signaling pathway. The latter effect, in contrast, was more pronounced, enhancing the TNFalpha-stimulated NF-kappaB-dependent transcription by more than sevenfold. This positive effect was NF-kappaB-specific, and was eliminated by mitogen-activated protein kinase (MAPK) inhibitors. Altogether, our data suggest that insulin has short-term anti-inflammatory but long-term proinflammatory effects. From a clinical standpoint, this implies that low basal and periodically high plasma insulin is beneficial, whereas a sustained rise in plasma insulin, as often seen in patients with obesity, may induce atherothrombotic disorders, because of the NF-kappaB-mediated overexpression of proinflammatory/procoagulant/antifibrinolytic proteins in the liver.
Iwasaki
Yasumasa
Y
Department of Endocrinology, Metabolism, and Nephrology, Kochi Medical School, Kochi University, Nankoku 783-8505, Japan. iwasakiyasumasa@gmail.com
Nishiyama
Mitsuru
M
Taguchi
Takafumi
T
Asai
Masato
M
Yoshida
Masanori
M
Kambayashi
Machiko
M
Terada
Yoshio
Y
Hashimoto
Kozo
K
D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007249:Inflammation / Q000139:chemically induced* / Q000235:genetics / Q000517:prevention & control*; D018836:Inflammation Mediators / Q000494:pharmacology; D007328:Insulin / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008954:Models, Biological; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D011972:Receptor, Insulin / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D013997:Time Factors; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured
D000893:Anti-Inflammatory Agents; D007004:Hypoglycemic Agents; D018836:Inflammation Mediators; D007328:Insulin; D016328:NF-kappa B; D011972:Receptor, Insulin